RU2534903C1 - Macrocyclic alkylammonium derivatives of 6-methyluracil having anticholinesterase activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel macrocyclic alkylammonium derivatives of 6-methyluracil of formula (1). The compounds have anticholinesterase activity and can be used for pharmacological correction of synaptic defects which cause Alzheimer's disease, myasthenia gravis and other forms of pathological muscle weakness. The compounds can be used when treating glaucoma, intestinal atony, alcoholism, schizophrenia, manic-depressive psychosis, traumatic brain injury, sleep disorders, etc. In formula (1)

X=NO₂, Y=(CH₂)₄ (1a); X=CN, Y=(CH₂)₄ (1b); X=NO₂, Y=C₆H₄ (1c); X=CN, Y=C₆H₄ (1d).

EFFECT: improved properties of compounds.

2 cl, 2 tbl, 9 ex

Description

The invention relates to the organic chemistry of heterocyclic compounds, in particular to macrocyclic alkylammonium derivatives of 6-methyluracil of formula (1), which have the property of inhibiting cholinesterase activity and can find application in medicine and veterinary medicine.

where X = NO ₂ , Y = (CH ₂ ) ₄ (1a);

X = CN, Y = (CH ₂ ) ₄ (1b);

X = NO ₂ , Y = C ₆ H ₄ (1c);

X = CN, Y = C ₆ H ₄ (1d).

Cholinesterase inhibitors are widely used in medical practice for the pharmacological correction of synaptic defects underlying Alzheimer's disease, myasthenia gravis and other forms of pathological muscle weakness. Their effectiveness has also been shown in the treatment of glaucoma, intestinal atony, traumatic brain injuries, alcoholism, manic-depressive psychoses, schizophrenia, senile dementia, autism, sleep disorders, etc. The pharmaceutical industry produces many anticholinesterase drugs: Aminostigmine, Deoxypeganine, Distolamin, Stefaglabrin , Oxazil, Pyridostigminebromide, Proserin, Galantamine, Physostigmine. Depending on the chemical structure and physicochemical properties, anticholinesterase drugs differ among themselves, for example, tertiary amines (physostigmine, galantomine, etc.) penetrate biological membranes, including through the blood-brain barrier, and have a pronounced effect on the central nervous system. Since the mid-90s of the last century, acetylcholinesterase inhibitors as substances that improve cognitive function have been used in the treatment of patients with mild or moderate severity of Alzheimer's disease. Quaternary ammonium derivatives (proserin, pyridostigmine bromide, oxazyl, etc.) are difficult to penetrate the blood-brain barrier and are thus used to correct defects in synaptic transmission in peripheral synapses (mainly in the treatment of myasthenia gravis and other forms of pathological muscle weakness).

A disadvantage of most known anticholinesterase drugs used in the treatment of muscle weakness is the lack of selectivity for the enzymes acetylcholinesterase and butyrylcholinesterase. Butyrylcholinesterase is predominantly present in the blood and its inhibition does not have a positive effect in the treatment of defects in synaptic transmission of excitation by cholinesterase inhibitors. Since the inhibition of acetylcholinesterase has a target effect, there is no need to suppress the function of butyrylcholinesterase. However, currently used in the treatment of myasthenic syndromes of cholinesterase inhibitor (Kalimin and Neostigmine) are not selective for these two enzymes.

The studies conducted by the authors revealed a new class of cholinesterase inhibitors - tetraalkylammonium derivatives of 6-methyluracil, which are capable of highly selectively blocking mammalian acetylcholinesterase [Doklady RAS. - 1998. - T.362, No. 1. P.68-70: Reports of the Russian Academy of Sciences. - 2001. - T.376, No. 6. - S.818-822; Modern toxicol problems. - 2004. - No. 3. - S.25-33; RAS reports. - 2005. - T.401, No. 1. - S. 120-123; Chem. farm. g. - 2005. - T.39, No. 5. - S.15-19; Modern toxicol issues. - 2006. - No. 2. - S.13-22].

It is known that 6-methyluracil and its derivatives are physiologically active substances and are widely used in medical practice. For example, the drugs Methyluracil and Pentoxyl have anabolic activity. These drugs accelerate cell regeneration processes; contribute to wound healing, stimulate cellular and humoral factors of immunity. In addition to the ability to stimulate leukopoiesis and erythropoiesis, drugs created on the basis of methyluracil and pentoxil also revealed other properties - increase phagocytosis, resistance to infection, post-vaccination immunity, stimulate reparative processes, have anti-inflammatory effects, cause anabolic and anti-catabolic effects, immunostimulating etc. Antitoxic and antioxidant, membrane stabilizing properties were also found.

The most structurally close to the claimed compounds of formula (1) are pyrimidinophanes (macrocyclic pyrimidine derivatives) of formula (4) and (5) containing 6-methyluracil moieties and alkyl ammonium groups in their composition.

These compounds exhibit antimicrobial activity and possess cholinolytic properties, while they have no ability to inhibit acetylcholinesterase [Current problems of toxicology. - 2006. - N 2. - S.13-22; Eur. J. Med. Chem. - 2006. - Vol.41. - N 9. - P.1093-1101]. Among the 6-methyluracil derivatives known from the level containing alkyl ammonium groups, only acyclic compounds possess anticholinesterase properties [Chemico-biological interactions. - 2008 .-- Vol. 175. - Nos 1-3. - P.286-292].

Expanding the range of anticholinesterase agents based on tetraalkylammonium derivatives of 6-methyluracil is an object of the invention.

The technical result to which the invention is directed, are new cholinesterase inhibitors - macrocyclic alkylammonium derivatives of 6-methyluracil of the formula (1):

where X = NO ₂ , Y = (CH ₂ ) ₄ (1a);

X = CN, Y = (CH ₂ ) ₄ (1b);

X = NO ₂ , Y = C ₆ H ₄ (1c);

X = CN, Y = C ₆ H ₄ (ld).

It should be noted that the three claimed compounds (pyrimidinophan) are new, namely 1 (a), 1 (b) and 1 (d). The compound (1c), where X = NO ₂ , Y = C ₆ H ₄ described, however, not as an inhibitor of cholinesterase [Nikolaev A.E. Synthesis and structural features of pyrimidinophanes containing nitrogen or sulfur atoms in connecting bridges. / Diss. for the degree of Cand. Chem. sciences. - 2008].

The inventive compounds are obtained from pyrimidinophanes of the formula (3), which are synthesized by the cyclization of 1,3-bis (5-aminoethylpentyl-1) -6-methyluracil (2) 1,6-dibromhexane or para-dibromoxysylene according to the above scheme. Compound (2) and a method for its preparation are described [R.X. Giniyatullin, A.S. Mikhailov, V.E. Semenov et al. / Izv. AN Ser. Chem. - 2003. - T.52. - No. 7. - S.1511-1515]. The target compounds (1) were obtained by the interaction of pyrimidinophanes (3) with ortho-nitrobenzyl bromide or ortho-cyanobenzyl bromide in acetonitrile.

Scheme - Synthesis of compounds (pyrimidinophanes) of the formula (1)

Example 1. Synthesis of 7,14-Diaza-7,14-diethyl-1 ² , 1 ⁴ -dioxo-1 ^6- methyl-1 (3,1) -pyrimidine-cyclonone-decafane (3) Y = (CH ₂ ) ₄

To a suspension of 2.50 g (18.1 mmol) K ₂ CO ₃ in 100 ml of CH ₃ CN, stirred at 50-55 ° C, solutions of 2.30 g (6.5 mmol) of compound (2) in 25 ml of CH ₃ CN are simultaneously added dropwise over 1 h. and 1.78 g (7.2 mmol) of 1,6-dibromohexane in 25 ml of CH ₃ CN. Upon completion of the dropwise addition, the reaction mass was stirred at a temperature of 50-55 ° C for 8 h, after which it was evaporated in vacuo and 100 ml of CHCl _{3 was} added to the residue. The precipitate formed is filtered off, the filtrate is concentrated and chromatographed through a column of SiO ₂ . The column is washed sequentially with petroleum ether, ethyl acetate, ethyl acetate-diethylamine (10: 1). After evaporation of the last eluate, 0.27 g (10%) of pyrimidinophan (3) is obtained, where Y = (CH ₂ ) ₄ as an oil.

¹ H NMR spectrum (600 MHz) in CDCl ₃ , δ, ppm: 1.00-1.02 (m, 6H), 1.32-1.38 (m, 8H), 1.44-1.52 (m, 8H), 1.64 -1.66 (m, 4H), 2.22 (s, 3H), 2.39-2.41 (m, 8H), 2.48-2.50 (m, 4H), 3.83 (t, 2H, J = 7.3 Hz), 3.94 ( t., 2H, J = 7.0 Hz), 5.55 (s, 1H).

Mass spectrum (EU, 70 eV), m / z (I _rel (%)): 435 (10), 434 [M] ⁺ (31), 419 [M-15] ⁺ (25), 405 [M- 29] ⁺ (100), 140 (21), 99 (30);

IR spectrum (oil), ν, cm ^-1 : 2932 s, 2858 s, 2798 s, 1701 s, 1662 s.p., 1467 s., 1431 s., 1399 s., 1365 s. , 1207 words, 1156 pages, 1071 words, 1018 words, 815 words, 768 words

Gross formula C ₂₅ H ₄₆ N ₄ O ₂ . Calculated,%: C 69.08, H 10.67, N 12.89.

Found,%: C 69.00, H 10.75, N 12.85.

Found: m / z 434.3621 [M] ⁺ . C ₂₅ H ₄₆ N ₄ O ₂ . Calculated: M = 434.36209.

Example 2. Synthesis of 7,14-Diazonium-7,14-diethyl-7,14-di-ortho-nitrobenzyl-1 ² , 1 ⁴ -dioxo-1 ⁶ -methyl-1 (3,1) -pyrimidine acyclone-decafandibromide (1a)

To a solution of 0.15 g (0.70 mmol) of ortho-nitrobenzyl bromide in 40 ml of CH ₃ CN was added 0.15 g (0.35 mmol) of pyrimidinophan (3), where Y = (CH ₂ ) ₄ and stirred at a temperature of 50-60 ° C for 10 h The solvent is evaporated. The residue was triturated thoroughly in anhydrous diethyl ether and the ether was decanted. The procedure is repeated several times until a crystalline substance is obtained, which is then dried in vacuum (0.1 mmHg).

Received 0.27 g (90%) of the target compound (1a), which is a yellowish crystalline substance, so pl. 120 ° C.

¹ H NMR spectrum (400 MHz) in CDCl ₃ , δ, ppm: 1.18-1.22 (m, 6H), 1.36-1.85 (m, 20H), 2.25 (s, 3H), 3.27-3.50 (m, 12H), 3.78-3.80 (m, 2H), 3.95-3.97 (m, 2H), 4.84 (br s, 4H), 5.58 (s, 1H), 7.49-8.05 (m ., 8H);

IR spectrum (KBr), ν, cm ^-1 : 2945 s, 2864 s, 1694 s, 1655 s, 1528 s, 1470 s, 1432 s, 1350 s, 1204 f., 1144 f., 1078 f., 1037 f., 923 f., 858 f., 768 f., 726 s.

The gross formula is C ₃₉ H ₅₈ Br ₂ N ₆ O ₆ . Calculated,%: C 54.04, H 6.75, N 9.70, Br 18.44. Found,%: C 54.10, H 6.82, N 9.81, Br 18.54.

MALDI-TOF mass spectrum: calculated for C ₃₉ H ₅₈ Br ₂ N ₆ O ₆ [M-2Br] ⁺ , [M-2Br-C ₇ H ₆ NO ₂ ] ⁺ 706.4, 570.4, respectively. Found: 706.6, 570.4.

Example 3. Synthesis of 7,14-Diazonium-7,14-diethyl-7,14-di-ortho-cyanobenzyl-1 ² , 1 ⁴ -dioxo-1 ⁶ -methyl-1 (3,1) -pyrimidine-cyclone nadecafandibromide (1b) carry out analogously to example 2 of 1.12 g (0.28 mmol) of pyrimidinophan (3), where Y = (CH ₂ ) ₄ and 0.14 g (0.71 mmol) of ortho-cyanobenzyl bromide. Received 0.22 g (88%) of the target compound (1b), which is a yellowish crystalline substance, so pl. 110 ° C.

¹ H NMR spectrum (400 MHz) in CDCl ₃ , δ, ppm: 1.17-1.20 (m, 6H), 1.44-1.90 (m, 20H), 2.26 (s, 3H), 3.38-3.68 (m, 12H), 3.78-3.80 (m, 2H), 3.95-3.97 (m, 2H), 4.64 (broad s, 4H), 5.58 (s, 1H), 7.42-7.82 (m. , 8H);

IR spectrum (KBr), ν, cm ^-1 : 2946 s, 2862 s, 2226 sr, 1694 s, 1655 s.p., 1467 s., 1432 s., 1401 s., 1213 s. 1161 words, 1034 words, 770 pages

The gross formula is C ₄₁ H ₅₈ Br ₂ N ₆ O ₂ . Calculated,%: C 59.56, H 7.07, N 10.17, Br 19.33. Found,%: C 59.70, H 7.12, N 10.08, Br 19.40.

MALDI-TOF mass spectrum: calculated for C ₄₁ H ₅₈ Br ₂ N ₆ O ₂ [M-Br] ⁺ , [M-2Br-C ₈ H ₆ N] ⁺ 746.9, 550.4, respectively. Found: 746.6, 550.3.

Example 4. Synthesis of 7,11-Diaza-7,11-diethyl-1 ² , 1 ⁴ -dioxo-1 ^6- methyl-1 (3,1) -pyrimidine-9 (1,4) -benzenecyclohexadecafane (3) Y = C ₆ H ₄

To a solution of 2.07 g (5.88 mmol) of compound (2) in 100 ml of CH ₃ CN, 1.62 g (11.76 mmol) of K ₂ CO ₃ and 1.67 g (6.33 mmol) of para-dibromo xylene are added. The reaction mass is stirred for 10 hours at a temperature of 70 ° C. The reaction mixture was cooled, the solvent was distilled off, and 100 ml of CHCl _{3 was} added to the residue. The precipitate formed is filtered off, the filtrate is concentrated and chromatographed through an Al ₂ O ₃ column. The column was washed sequentially with diethyl ether and diethyl ether-ethyl acetate-diethylamine (10: 10: 1). After evaporation of the last eluate, 0.60 g (22%) of pyrimidinophan (3) is obtained, where Y = C ₆ H ₄ as an oil.

¹ H NMR spectrum (600 MHz) in CDCl ₃ , δ, ppm: 1.06-1.10 (m, 6H), 1.22-1.27 (m, 4H), 1.38-1.41 (m, 4H), 1.48 -1.55 (m, 4H), 2.20 (s, 3H), 2.25-2.28 (m, 4H), 2.56-2.59 (m, 4H), 3.52 (s, 2H), 3.54 (s, 2H) 3.75 (t, 2H, J = 7.3 Hz), 3.89 (t, 2H, J = 6.8 Hz), 5.53 (s, 1H), 7.22-7.26 (m, 4H);

Mass spectrum (EU, 70 eV), m / z ( _Irel (%)): 455 [M + 1] ⁺ (8), 454 [M] ⁺ (36), 439 [M-15] ⁺ (25) , 426 (45), 425 [M-29] ⁺ (100), 382 (13), 349 (27), 162 (16), 148 (18), 145 (40), 132 (14), 112 (14 ), 109 (20), 105 (34), 104 (87);

IR spectrum (oil), ν, cm ^-1 : 2964 words, 2932 pages, 2859 words, 2798 words, 1702 pages, 1662 pages, 1467 pages, 1431 pages, 1399 pages , 1365 words, 1207 words, 1156 pages, 1071 words, 1019 words, 849 words, 815 words, 765 words Found,%: C 71.47, H 9.22, N 12.21.

Gross formula C ₂₇ H ₄₂ N ₄ O ₂ . Calculated,%: C 71.33, H 9.31, N 12.32.

Found: m / z 454.3307 [M] ⁺ . C ₂₇ H ₄₂ N ₄ O ₂ . Calculated: M = 454.33078.

Example 5. Synthesis of 7,11-Diazonium-7,11-diethyl-7,11-di-ortho-nitro-benzyl-1 ² , 1 ⁴ -dioxo-1 ^6- methyl-1 (3,1) -pyrimidine- 9 (1,4) -benzinacyclohexadecafandibromide (1c) is carried out analogously to example 2 of 0.40 g (0.88 mmol) of pyrimidinophan (3), where Y = C ₆ H ₄ and 0.42 g (1.94 mmol) of ortho-nitrobenzyl bromide in 60 ml of CH ₃ CN.

Received 0.57 g (74%) of the target compound (1c), which is a yellowish crystalline substance, so pl. 250-251 ° C.

¹ H NMR spectrum (600 MHz) in CDCN ₃ , δ, ppm: 1.14-1.11 (m, 6H), 1.20-1.80 (m, 12H), 2.21 (s, 3H), 2.94-3.21 (m. , 8H), 3.70-3.90 (m, 4H), 4.44-4.86 (m, 8H), 5.48 (s, 1H), 7.56-7.78 (m, 8H).

The gross formula is C ₄₁ H ₅₄ Br ₂ N ₆ O ₆ . Calculated,%: C 55.53, H 6.14, Br 18.02, N 9.48. Found,%: C 55.45, H 6.06, Br 18.11, N 9.46.

MALDI-TOF mass spectrum: calculated for C ₄₁ H ₅₄ Br ₂ N ₆ O ₆ [M-Br] ⁺ , [M-2Br-C ₇ H ₆ NO ₂ ] ⁺ 805.3, 590.4, respectively. Found: 805.2, 590.3.

Example 6. Synthesis of 7,11-diazonium-7,11-diethyl-7,11-di-ortho-cyano-benzyl-1 ² , 1 ⁴ -dioxo-1 ^6- methyl-1 (3,1) -pyrimidine- 9 (1,4) -benzinacyclohexadecafandibromide (1d) is carried out analogously to example 2 from 0.28 g (0.62 mmol) of pyrimidinophan (3), where Y = C ₆ H ₄ and 0.25 g (1.28 mmol) of ortho-cyanobenzyl bromide. Received 0.36 g (70%) of the target compound (1d), which is a yellowish crystalline substance, so pl. 143-145 ° C.

¹ H NMR spectrum (600 MHz) in DMSO-d ₆ , δ, ppm: 1.11-1.141 (m, 6H), 1.24-1.75 (m, 12H), 2.28 (s, 3H), 3.00-3.30 ( m., 8H), 3.70-3.90 (m, 4H), 4.60-4.96 (m, 8H), 5.58 s (s, 1H), 7.65-8.05 (m, 8H).

The gross formula is C ₄₃ H ₅₄ Br ₂ N ₆ O ₂ . Calculated,%: C 60.99, H 6.43, Br 18.87, N 9.93. Found,%: C 60.90, H 6.46, Br 18.93, N 10.00.

MALDI-TOF mass spectrum: calculated for C ₄₃ H ₅₄ Br ₂ N ₆ O ₂ [M-Br] ⁺ , [M-2Br-C ₈ H ₆ N] ⁺ 765.3, 570.4, respectively. Found: 765.3, 570.2.

The inventive alkylammonium derivatives of 6-methyluracil of the formula (1) are yellowish crystalline substances soluble in water, dimethyl sulfoxide, acetonitrile, chloroform.

Biological activity

Example 7. Determination of anticholinesterase activity of pyrimidinophanes of the formula (1)

Enzymatic reactions were recorded according to Elman’s method [Ellman GL, Courtney KD, Andres V. Jr., Feather-Stone RM A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961, No. 7, C.88-95]. The analysis of the dependence of cholinesterase activity on the concentration of the inhibitor was carried out by the Hill equation with the calculation of the average effective concentration - IC ₅₀ . Human acetylcholinesterase and human butyrylcholinesterase were purchased from Sigma-Aldrich. The results of the inhibitory activity of the claimed compounds are shown in table 1, which indicate that all compounds showed high anticholinesterase activity, showing greater efficacy against acetylcholinesterase (AChE) compared with butyrylcholinesterase (BChE). Compound 1 (c) is a leader in the studied group of alkylammonium derivatives of 6-methyluracil of formula (1), because its ACE inhibitory concentration (IC ₅₀ ) is an order of magnitude lower than that of compounds 1 (a), 1 (b), or 1 (d).

Table 1 Anticholinesterase activity and toxicity of compounds of the formula (1) Compound (molecular weight) AChE of human red blood cells IC ₅₀ , [M] BChE of human serum, IC ₅₀ , [M] LD ₅₀ mg / kg (mice, ip) 1 (a) (M.M. 866.0) 5.9 × 10 ^-8 5.0 × 10 ^-6 6.50 (4.87 ÷ 7.85) 1 (b) (M.M. 826.0) 9.8 × 10 ^-8 6.0 × 10 ^-6 7.00 (6.104 ÷ 8.69) 1 (s) (M.M. 886.0) 7.0 × 10 ^-9 1.2 × 10 ^-6 3.74 (2.924 ÷ 4.47) 1 (d) (M.M. 846.7) 2.8 × 10 ^-8 3.5 × 10 ^-7 2.81 (2.394 ÷ 3.30)

Example 8. The study of the general toxic effect of the claimed compounds was carried out according to the "Methodological guidelines for the study of the general toxic effect of pharmacological substances" (M., Medicine. 2005. Edited by R.U. Khabriev) on outbred white mice of both sexes weighing 19.0 ± 2, 0 g contained in a standard diet in natural conditions lighting the room at room temperature. The toxicological evaluation data for the compounds are shown in Table 1. For comparison, the LD _{50 of} Pyridostigmine Bromide (anticholinesterase) for mice for oral administration is 12-15 mg / kg, and for intraperitoneal administration is 3 mg / kg of body weight. [http://www.mosmed.ru/medic/preparats/astamedica/kalimin/kaliminl1.htm]

Thus, the claimed alkylammonium derivatives of 6-methyluracil (1) has a high anticholinesterase activity with toxicity comparable with Pyridostigmine.

Example 9. Therapy of symptoms of muscle weakness in an experimental autoimmune model of myasthenia gravis

Compound 1 (c), which exhibits the highest in vitro anticholinesterase activity, was tested by us in vivo for the ability to stop the signs of muscle weakness in animals with experimental Gravis myasthenia. An experimental autoimmune model of myasthenia gravis (EAMG) was created according to the method described in [Baggi F, Annoni A, Ubiali F, Milani M, Longhi R, Scaioli W, Cornelio F, Mantegazza R, Antozzi C. Breakdown of tolerance to a self- peptide of acetylcholine receptor alpha-subunit induces experimental myasthenia gravis in rats. J Immunol. 2004 Feb 15; 172 (4): 2697-703].

The development of muscle weakness was diagnosed by the presence of a pronounced decrement of the amplitude of the integral action potential (PD) of the rat hind limb muscle during high-frequency stimulation of the sciatic nerve (40 Hz, 200 stimuli). Sciatic nerve stimulation was performed with needle electrodes. The integral PD of muscles was recorded with cutaneous electrodes from the surface of the hind limbs of rats.

table 2 The decrement of the amplitude of muscle action potential in healthy animals and animals with EAMG The ratio of the amplitudes of the first PD to the 200th PD (decrement),% healthy animals animals with myasthenia gravis Water 95.02 ± 1.09 67.31 ± 2.72 Compound 1 (c) 0.1 mg / kg - 75.05 ± 1.83 Compound 1 (c) 0.3 mg / kg - 95.42 ± 0.97 Pyridostigmine 0.1 mg / kg - 91.27 ± 1.90

After the diagnosis of EAMG, three groups of rats were injected intraperitoneally with either an aqueous solution of compound 1 (c), or pyridostigmine bromide (Sigma-Aldrich) - the active substance of the preparations Kalimin and Mestinon, or the equivalent volume of water for injection only (OJSC Semashko Moskhimpharmpreparaty )

In experiments on animals with experimental myasthenia gravis, a dose of compound 1 (c) was selected that restored the value of the decrement of the amplitude of the integral muscle PD to the indices of healthy animals. This dose was 0.3 mg / kg with intraperitoneal administration. A similar effect was achieved by injection of Pyridostigmine at a dose of 0.1 mg / kg (table 2). This fact makes compound 1 (c) a promising candidate as a treatment for pathological muscle weakness syndromes.

New effective inhibitors of the enzyme acetylcholinesterase are proposed, which can be used in veterinary medicine and medicine, for example, for the treatment of myasthenia gravis and other forms of pathological muscle weakness.

Claims (2)

1. Macrocyclic alkylammonium derivatives of 6-methyluracil of the general formula:

where X = NO ₂ , Y = (CH ₂ ) ₄ ;
X = CN, Y = (CH ₂ ) ₄ ;
X = CN, Y = C ₆ H _4. 2. Macrocyclic alkylammonium derivatives of 6-methyluracil of the general formula:

where X = NO ₂ , Y = (CH ₂ ) ₄ ;
X = CN, Y = (CH ₂ ) ₄ ;
X = NO ₂ , Y = C ₆ H ₄ ;
X = CN, Y = C ₆ H ₄ ,
possessing anticholinesterase activity.